Bibliographic details of the publications referred to by author in this specification are collected at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other country.
The increasing sophistication of organic synthesis including combinatorial chemistry and recombinant DNA processes is greatly facilitating research and development in the chemical and biological industries. Of particular importance are the rapidly growing industries involving diagnostic and screening processes. Such processes are useful for diagnosing a range of human and animal disease conditions or hereditary traits. Furthermore, natural product screening is now considered a fundamental approach for identifying potentially new therapeutic agents.
Central to developing diagnostic and screening processes is the need for suitable solid supports as well as matrices for combinatorial chemical processes and immunological, biochemical and/or nucleic acid interactions.
High throughput parallel synthesis and/or combinatorial chemistry approaches to compound synthesis have dramatically changed the process of identifying and optimizing drug discovery. With these methodologies, large sets of compounds are synthesized in parallel as discrete compounds or as mixtures. Methodologies include solid phase synthesis as well as solution phase processing some of which use solid phase reagents and/or scavengers as part of the synthesis process. Methods which include parallel synthesis of individual compounds are preferred over synthesis in mixtures. In terms of numbers of compounds handled in parallel, solid phase methodologies have greater advantages than solution phase methods.
There are a number of methods for the parallel synthesis of discrete compounds by solid phase methodologies. One approach is the “Split and Combine” method of synthesis. Here, large numbers of individual beads are equally divided into separate reaction vessels and each is reacted with a single different reactor. After completion of the reactions and subsequent washings to remove excess reagents, the individual resin beads are recombined and mixed thoroughly and redivided into separate reaction vessels. Reactions with a further set of reagents gives a complete set of possible dimeric sets as mixtures. The process may be repeated as required.
One example of solid phase synthesis is conducted on membranes. International Patent Publication No. WO 90/02749 discloses the use of a polymer substrate and in particular polyethylene substrate to synthesize peptides. The polyethylene substrate is generally in the form of a sheet or film to which polystyrene chains have been grafted.
High Throughput Screening (HTS) is a method where many compounds are tested in parallel for biological activity. Currently, the most widely established techniques utilize 96-well microtitre trays, where 96 independent tests can be performed simultaneously on a single plastic plate containing 96 individual wells. Parallel handling of such trays allows simultaneous testing of many thousands of individual samples. The wells of a 96-well microtitre tray can handle volumes from 50 to 500 μl. A major focus has been directed to improving HTS output by making the wells smaller to create 384- and 1536-well formats within the same microtitre plate dimensions.
In an alternative process, U.S. Pat. No. 5,976,813 describes a Continuous Format High Throughput Screening (CF-HTS). This process introduces multiple test samples into or onto a porous assay matrix. The central idea of this approach depends on separation of test samples by diffusion rather than within individual wells of a microtitre tray. As long as localization of the specific test sample is by diffusion, there will be significant variation in diffusion rate according to solvent solubility and compound characteristics. Such variations limit that accuracy of any assay readout. Furthermore, despite improvements in efficiency, CF-HTS still faces similar difficulties as in HTS.
Other examples include the use of radiofrequency plasma discharge to create functionalities such as amino groups directly onto the surface of polymers (U.S. Pat. No. 5,583,211). More general chemical oxidation methods are also used as starting points for microcontact-based patterning.
In work leading up to the present invention, the inventors sought to generate hybrid polymers for use in a range of applications including solid phase organic synthesis as well as a solid substrate for polymer (e.g. nucleic acid molecules, amino acid chains) binding and/or chemical interaction. The hybrid polymers comprise a population of homogenous or heterogenous polymers, generally in a random or patterned array on a substrate polymer. Physical stress means is required to be applied to the substrate polymer in order to permit grafting of the population of polymers to the substrate polymer.